Assessment of redundant randomized clinical trials among patients with ST segment elevation myocardial infarction.

BACKGROUND: Redundant clinical trials waste resources and unnecessarily put patients at risk for harm. The objectives of the study were to assess redundant randomized clinical trials (RCTs) conducted in mainland China or the USA among patients with ST segment elevation myocardial infarction (STEMI) and estimate the harm to patients enrolled in redundant RCTs. METHODS: We searched bibliographic databases for eligible RCTs comparing a routine therapy with a placebo or no treatment among patients with STEMI in mainland China or the United States. The routine therapy for STEMI included reperfusion (percutaneous coronary intervention or fibrinolytic therapy), P2Y12 receptor inhibitors, statins, and anticoagulants. Redundant RCTs were defined as those initiated or continued recruiting new patients 1 year after the experimental intervention was established as routine therapy in clinical practice guidelines. Cumulative meta-analyses were conducted to confirm the efficacy of these routine therapies. The primary outcome was the number of extra major adverse cardiac events (MACEs) attributable to the deprivation of routine therapies among patients in the control groups of redundant RCTs-that is, the number of extra MACEs that could have been prevented had these patients received routine therapy. RESULTS: Nine hundred eighty-three eligible RCTs conducted in mainland China were identified, of which 775 (78.8%) were redundant. None of the five eligible RCTs conducted in the United States were redundant. All redundant RCTs have reiterated the benefits of routine therapies for patients with STEMI, while none were cited by the 2019 clinical practice guideline for the management of STEMI. The 18,819 patients in the control groups of redundant RCTs experienced 3305 (95% CI: 3169-3441) extra MACEs, including 1091 (1014-1165) deaths, 576 (519-633) recurrent myocardial infarctions, 31 (19-42) revascularizations, 39 (23-54) strokes, 744 (679-810) heart failures, and 823 (754-893) patients with recurrent or exacerbated angina pectoris. Cumulative meta-analyses confirmed the efficacy of the routine therapies among patients in mainland China and supported using practice guidelines to define redundant RCTs. CONCLUSIONS: Redundant RCTs conducted in mainland China have resulted in unnecessary MACEs among patients with STEMI. While the reasons behind redundant RCTs need to be further investigated, these results suggest potential research waste and violation of research ethics.

Association of dietary inflammatory index with helicobacter pylori infection and mortality among US population.

BACKGROUND: Limited research has been conducted on the potential relationship between the dietary inflammation index (DII) and mortality, particularly in individuals with Helicobacter pylori (H. pylori) infection. This study aimed to investigate the association between the DII and H. pylori infection, as well as their respective impacts on all-cause mortality in a cohort of individuals with or without H. pylori infection. METHODS: Data from the 1999-2018 National Health and Nutrition Examination Survey (NHANES) were utilized for this study, with a final of 4370 participants included. Both univariable and multivariable-adjusted logistic regression analyses were employed to explore the relationship between H. pylori infection and pertinent covariates. Cox regression analysis, as well as restricted regression cubic spline analysis, were utilized to assess the association between DII and all-cause mortality among individuals with or without H. pylori infection. RESULTS: The findings demonstrated a positive correlation between DII scores and H. pylori infection, even after adjusting for potential confounding factors. Moreover, higher DII scores were significantly associated with an elevated risk of mortality exclusively in individuals with H. pylori infection, while no such association was observed in the uninfected population. Additional analysis using restricted cubic spline modeling revealed a positive linear relationship between DII scores as a continuous variable and the adjusted risk of all-cause mortality specifically in H. pylori-infected patients. CONCLUSION: The results of this study indicated that DII was positively correlated with an increased risk of H. pylori infection and was associated with a heightened risk of all-cause mortality solely in individuals with H. pylori infection. Consequently, DII might serve as a useful tool for risk stratification in the H. pylori-infected population among U.S. adults. Further research is warranted to elucidate the underlying mechanisms and potential clinical implications of these findings.

The impact of the stress hyperglycemia ratio on mortality and rehospitalization rate in patients with acute decompensated heart failure and diabetes.

BACKGROUND: The relationship between stress hyperglycemia and long-term prognosis in acute decompensated heart failure (ADHF) patients is unknown. This study investigated the associations of stress hyperglycemia with mortality and rehospitalization rates among ADHF patients with diabetes. METHODS: We consecutively enrolled 1904 ADHF patients. Among them, 780 were with diabetes. Stress hyperglycemia was estimated using the stress hyperglycemia ratio (SHR), which was calculated by the following formula: SHR = admission blood glucose/[(28.7 × HbA1c%) - 46.7]. All diabetic ADHF subjects were divided into quintiles according to the SHR. The primary endpoint was all-cause death at the 3-year follow-up. The secondary endpoints were cardiovascular (CV) death and heart failure (HF) rehospitalization at the 3-year follow-up. A Cox proportional hazards model and restricted cubic spline analysis were used to elucidate the relationship between the SHR and the endpoints in diabetic ADHF patients. Further analyses were performed to examine the relationships between SHR and the outcomes in heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). RESULTS: A total of 169 all-cause deaths were recorded during a median follow-up of 3.24 years. Restricted cubic spline analysis suggested a U-shaped association between the SHR and the mortality and rehospitalization rates. Kaplan-Meier survival analysis showed the lowest mortality in the 2nd quintile (P = 0.0028). Patients categorized in the highest range (5th quintile) of SHR, compared to those in the 2nd quintile, exhibited the greatest susceptibility to all-cause death (with a hazard ratio [HR] of 2.76 and a 95% confidence interval [CI] of 1.63-4.68), CV death (HR 2.81 [95% CI 1.66-4.75]) and the highest rate of HF rehospitalization (HR 1.54 [95% CI 1.03-2.32]). Similarly, patients in the lowest range (1st quintile) of SHR also exhibited significantly increased risks of all-cause death (HR 2.33, 95% CI 1.35-4.02) and CV death (HR 2.32, 95% CI 1.35-4.00). Further analyses indicated that the U-shape association between the SHR and mortality remained significant in both HFpEF and HFrEF patients. CONCLUSION: Both elevated and reduced SHRs indicate an unfavorable long-term prognosis in patients with ADHF and diabetes.

High triglyceride-glucose (TyG) index is associated with poor prognosis of heart failure with preserved ejection fraction.

BACKGROUND: The impact of insulin resistance on the prognosis of heart failure with preserved ejection fraction (HFpEF) remains unknown. This study aimed to investigate the association between the triglyceride-glucose (TyG) index, an easily calculated marker of insulin resistance, and the long-term prognosis of HFpEF. METHODS: A total of 823 patients with HFpEF were enrolled in the study. The TyG index was determined using the formula ln(fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). The primary endpoint was all-cause death. The secondary endpoints were cardiovascular (CV) death and heart failure (HF) rehospitalization. Restricted cubic spline, multivariate Cox proportional hazard models, and competing risk models were used for analyses. RESULTS: During a median follow-up period of 3.16 years, 147 (17.8%) all-cause deaths, 139 (16.8%) CV deaths, and 222 (27.0%) HF rehospitalizations occurred. Restricted cubic spline analysis revealed a J-shaped association between the TyG index and the mortality and rehospitalization rates. In the multivariate Cox proportional hazard models, compared with those in the lowest TyG index tertile, patients in the highest tertile exhibited the greatest susceptibility to all-cause death (HR 1.53, 95% CI 1.19-1.98) and CV death (HR 1.52, 95% CI 1.19-1.96). In the competing risk model, a significant association between the TyG index and HF rehospitalization was observed (HR 1.31, 95% CI, 1.07-1.61). CONCLUSION: A high TyG index is associated with an increased risk of mortality and rehospitalization in patients with HFpEF. The TyG index may serve as a promising prognostic marker for patients with HFpEF.

Short sleep duration and the risk of nonalcoholic fatty liver disease/metabolic associated fatty liver disease: a systematic review and meta-analysis.

PURPOSE: It is unclear whether or not nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated fatty liver disease (MAFLD) is related to short sleep duration. A meta-analysis was conducted to determine if inadequate sleep time increased the risk of NAFLD/MAFLD. METHODS: A comprehensive systematic literature review was conducted in the Embase, PubMed, and Cochrane Library databases from inception to August 1, 2022. Studies examining the correlation between inadequate sleep time and the risk of NAFLD/MAFLD were included. We pooled the odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. RESULTS: This meta-analysis included fifteen studies involving a total of 261,554 participants. In the pooled analysis, short sleep duration was found to be strongly correlated with an increased risk of NAFLD/MAFLD (OR, 1.15; 95% CI, 1.04-1.28; P = 0.01), with a moderate degree of heterogeneity between studies (I2 = 71.92%, Q = 49.87, P < 0.01). The sensitivity analysis suggested that the primary outcome was robust, and there was no significant publication bias. CONCLUSION: This meta-analysis indicates that inadequate sleep duration is strongly correlated with an elevated risk of NAFLD/MAFLD. The findings suggest that obtaining an adequate amount of sleep may be useful for preventing NAFLD/MAFLD, which is especially important given the low rate of response to pharmacotherapy.

Atherogenic index of plasma for non-diabetic, coronary artery disease patients after percutaneous coronary intervention: a prospective study of the long-term outcomes in China.

BACKGROUND: Non-diabetic coronary artery disease (CAD) patients are thought to encounter metabolic dysfunction and while these changes may be imperceptible to the patient they probably influence outcomes. At present, there is no system to support patients sensing these subtle changes, nor is there an established model for prognoses. The Atherogenic Index of Plasma (AIP) index has already proven useful for atherosclerosis although further research is needed, especially for those without hyperglycemia. METHODS: This is a prospective study of 5538 non-diabetic CAD patients who had received percutaneous coronary intervention (PCI). Participants were assigned to one of three groups according to their AIP index. High AIP index cases were then compared to low index patients according to major adverse cardiac events (MACE). Restricted cubic spline (RCS) analysis was also conducted to investigate interrelations between AIP index levels and hazard ratios (HR) for MACEs. RESULTS: Patients with a high AIP index encountered metabolic dysfunction compared to those with a low AIP index i.e., higher Body Mass Index (BMI), Total Cholesterol (TC), Triglycerides (TG), and uric acid as well as lower HDL-C. Each of the aforementioned interrelations were significant with p values of less than 0.001. There was also a significant increase in the number of MACEs in the high AIP index group compared to the low AIP index group (HR: 1.37, 95% CI 1.04-1.81; p = 0.025). A J-shaped RCS curve highlighted a change in the HR after the 0.18 juncture (HR per SD: 1.20, 95% CI 0.96-1.50). Further subgroup analysis supported the main findings, all with HRs greater than one. CONCLUSION: The AIP index could be used in prognostics for non-diabetic CAD patients 2 years after PCI. The relationship between hazard ratio and the AIP index appears to be J-shaped. Although, further multi-center studies designed for non-diabetic patients with potential metabolic dysfunction should be conducted to determine the value of the AIP index.

Isoform-Selective HDAC Inhibitor Mocetinostat (MGCD0103) Alleviates Myocardial Ischemia/Reperfusion Injury Via Mitochondrial Protection Through the HDACs/CREB/PGC-1α Signaling Pathway.

ABSTRACT: Over the past decade, histone deacetylases (HDACs) has been proven to manipulate development and exacerbation of cardiovascular diseases, including myocardial ischemia/reperfusion injury, cardiac hypertrophy, ventricular remodeling, and myocardial fibrosis. Inhibition of HDACs, especially class-I HDACs, is potent to the protection of ischemic myocardium after ischemia/reperfusion (I/R). Herein, we examine whether mocetinostat (MGCD0103, MOCE), a class-I selective HDAC inhibitor in phase-II clinical trial, shows cardioprotection under I/R in vivo and in vitro, if so, reveal its potential pharmacological mechanism to provide an experimental and theoretical basis for mocetinostat usage in a clinical setting. Human cardiac myocytes (HCMs) were exposed to hypoxia and reoxygenation (H/R), with or without mocetinostat treatment. H/R reduced mitochondrial membrane potential and induced HCMs apoptosis. Mocetinostat pretreatment reversed these H/R-induced mitochondrial damage and cellular apoptosis and upregulated CREB, p-CREB, and PGC-1α in HCMs during H/R. Transfection with small interfering RNA against PGC-1α or CREB abolished the protective effects of mocetinostat on cardiomyocytes undergoing H/R. In vivo, mocetinostat was demonstrated to protect myocardial injury posed by myocardial I/R via the activation of CREB and upregulation of PGC-1α. Mocetinostat (MGCD0103) can protect myocardium from I/R injury through mitochondrial protection mediated by CREB/PGC-1α pathway. Therefore, activation of the CREB/PGC-1α signaling pathway via the inhibition of Class-I HDACs may be a promising new therapeutic strategy for alleviating myocardial reperfusion injury.

Association between liver fibrosis and thrombotic or bleeding events in acute coronary syndrome patients.

BACKGROUND: The prognostic implication of liver fibrosis in acute coronary syndrome (ACS) patients are scarce. We sought to evaluate whether liver fibrosis scores (LFS) were associated with thrombotic or bleeding events in patients with acute coronary syndrome. METHODS: We included 6386 ACS patients who underwent percutaneous coronary intervention (PCI). This study determined liver fibrosis with aspartate aminotransferase to platelet ratio index (APRI), aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT ratio), Forns score, and nonalcoholic fatty liver disease fibrosis score (NFS). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause mortality (ACM), myocardial infarction (MI), and ischemic stroke (IS). RESULTS: During the follow-up, 259 (4.06%) MACCE and 190 (2.98%) bleeding events were recorded. As a continuous variable or a categorical variable stratified by the literature-based cutoff, LFS was positively associated with MACCE (p > 0.05) but not with bleeding events. Compared with subjects with low APRI scores, AST/ALT ratio scores, Forns scores, and NFS scores, subjects with high scores had a 1.57- to 3.73-fold increase risk of MACCE after adjustment (all p < 0.05). The positive relationship between LFS and MACCE was consistent in different subgroups. CONCLUSIONS: In ACS patients, increased LFS predicted an elevated risk of thrombotic events but not bleeding. LFS may contribute to thrombotic risk stratification after ACS.

SAHA could inhibit TGF-ß1/p38 pathway in MI-induced cardiac fibrosis through DUSP4 overexpression.

Growing evidences have revealed that a histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA) has anti-fibrotic effect in different diseases. In this study, we first evaluated whether SAHA could suppress cardiac fibrosis. Mice with MI-induced cardiac fibrosis were treated with SAHA by intraperitoneal injection and their cardiac function was improved after SAHA treatment. Results of western blotting and qRT-PCR in heart tissues suggested that TGFß1/P38 pathway was activated in MI mice, and this effect was reversed by SAHA. Cell proliferation assay suggested that SAHA could suppress TGF-ß1-induced cardiac fibroblasts proliferation. Furthermore, results of western blotting and qRT-PCR in cardiac fibroblasts depicted that SAHA may exert its anti-fibrotic effect through inhibiting TGF-ß1-induced P38 phosphorylation by promoting DUSP4 expression. Our findings may substantiate SAHA as a promising treatment for MI-induced cardiac fibrosis.

Enantioselective [3 + 2] annulation of 4-isothiocyanato pyrazolones and alkynyl ketones under organocatalysis.

An asymmetric [3 + 2] annulation reaction of 4-isothiocyanato pyrazolones with alkynyl ketones in the presence of an organic catalyst derived from a cinchona alkaloid under mild conditions is realized. This protocol provides unprecedented expeditious access to a wide range of optically active spiro[pyrroline-pyrazolones] with various electronic properties in high yields with good to excellent enantioselectivities.

Diastereoselective synthesis of indolenine-based spiro[pyrazolone-4,2'-pyrrolidine] scaffolds via 1,3-dipolar cycloaddition of 4-aminopyrazolones, aldehydes, and indolenines.

In this work, we report a one-pot [3 + 2] cycloaddition of 4-aminopyrazolones, indolenines, and aldehydes. The reaction utilized in situ generated azomethine ylides as 1,3-dipoles and 2-alkenylindolenines as dipolarophiles affording indolenine-derived spiro[pyrazolone-4,2'-pyrrolidine] scaffolds with four contiguous stereocenters with excellent yields (up to 95%) and diastereoselectivities (up to >20 : 1 dr) under simple conditions. The in situ generation of azomethine ylides and dipolarophiles in one pot is a unique feature of this process.

Evaluation of a risk index for predicting short-term and long-term outcomes in patients with ST-elevation myocardial infarction.

OBJECTIVE: This study aimed to evaluate the usefulness of the admission risk index (RI) to predict short-term and long-term outcomes in a broad population with ST-elevation myocardial infarction (STEMI) using data from the Chinese Acute Myocardial Infarction Registry. BACKGROUND: The RI was developed as a simple tool to predict risk of death in STEMI patients. The performance in predicting short-term and long-term risk of death in Chinese patients receiving percutaneous coronary intervention and conservative treatment for STEMI remains unclear. METHODS: Age, heart rate (HR), and systolic blood pressure (SBP) were used to calculate RI using (HR×[age/10]2 )/SBP. We used the prediction tool to predict mortality over 12 months. RESULTS: The C-index of the admission RI for predicting in-hospital, 1-, 6-, and 12-months mortality were 0.78, 0.78, 0.78, and 0.77, respectively, compared with 0.75 of the Global Registry in Acute Coronary Events score. Based on the receiver operating characteristic curve analysis, the RI was categorized into quintiles for convenient clinical use, and it revealed a nearly 15-fold gradient of increasing mortality from 2.29 to 32.5% (p < .0001) while RI >34 had the highest mortality. By categorizing into five different risk groups, the short-term and long-term mortality of patients receiving different treatments could be distinguished. CONCLUSIONS: RI based on three routine variables and easily calculated by any medical practitioner is useful for predicting in-hospital and long-term mortality in patients with STEMI at the initial consultation with clinicians.

tert-Amino Effect-Promoted Rearrangement of Aryl Isothiocyanate: A Versatile Approach to Benzimidazothiazepines and Benzimidazothioethers.

A general and practical approach to benzimidazothiazepine and benzimidazothioether derivatives via an intramolecular nucleophilic addition/ring expansion rearrangement of aryl isothiocyanates promoted by the tert-amino effect has been developed. This reaction is catalyzed by low-cost camphorsulfonic acid and tolerates a broad substrate scope with complete atom economy. Structurally intriguing benzimidazothiazepine and benzimidazothioether products could be easily obtained by a simple operation in good to excellent yield (up to 98%).

Randomized Comparisons of Double-Dose Clopidogrel or Adjunctive Cilostazol Versus Standard Dual Antiplatelet in Patients With High Posttreatment Platelet Reactivity: Results of the CREATIVE Trial.

BACKGROUND: Patients undergoing percutaneous coronary intervention react differently to antiplatelet drugs. Those with low responsiveness to clopidogrel have a higher risk of cardiac ischemic events. The goal of this study is to conduct a head-to-head comparison of the safety and effectiveness of intensified antiplatelet therapies (either double-dose clopidogrel [DOUBLE] or adjunctive cilostazol [TRIPLE]) and conventional strategy (STANDARD) in patients after percutaneous coronary intervention. METHODS: In this single-center, randomized, controlled trial, we used thromboelastography, a platelet function test, to select 1078 patients undergoing percutaneous coronary intervention at high thrombotic risk and compared the intensified antiplatelet therapies with standard antiplatelet therapy. The primary outcome was the incidence of major adverse cardiac and cerebrovascular events at 18 months after percutaneous coronary intervention, defined as a composite of all-cause death, myocardial infarction, target vessel revascularization, or stroke. Bleeding Academic Research Consortium defined bleeding complications (types 1, 2, 3, or 5) were the safety end points. RESULTS: The primary end point occurred in 52 patients (14.4%) in the STANDARD group, 38 patients (10.6%) in the DOUBLE group, and 30 patients (8.5%) in the TRIPLE group (hazard ratio, 0.720; 95% confidence interval, 0.474-1.094, DOUBLE versus STANDARD; hazard ratio, 0.550; 95% confidence interval, 0.349-0.866, TRIPLE versus STANDARD). No significant difference in the rates of major bleeding (Bleeding Academic Research Consortium grade≥3) was found in the DOUBLE group (3.34% versus 1.93% in STANDARD, P=0.133) and the TRIPLE group (2.53% versus 1.93% in STANDARD, P=0.240). The rate of Bleeding Academic Research Consortium-defined minor bleeding increased in the DOUBLE group (27.4% versus 20.3% in STANDARD, P=0.031), but not in the TRIPLE group (23.6% versus 20.3% in STANDARD, P=0.146). CONCLUSIONS: In patients with low responsiveness to clopidogrel, as measured by thromboelastography, the intensified antiplatelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding. Decreased trend of negative outcomes could be observed in patients with double dosage of clopidogrel, but the difference was not significant. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01779401.

Two common mutations within CYP2C19 affected platelet aggregation in Chinese patients undergoing PCI: a one-year follow-up study.

The effect of dual antiplatelet therapy, clopidogrel combined with aspirin, was influenced by CYP2C19 gene mutation and heterogeneity of population. Related studies remained controversial and limited, especially in Chinese. Total 3295 unrelated ACS Chinese patients undergoing percutaneous coronary intervention (PCI) were recruited and followed up to 1 year. Meanwhile, baseline and clinical data were retrieved. CYP2C19*2 and *3 were genotyped by sequencing. Associations of variants and metabolic types with platelet reactivity (PR) were analyzed by a logistic regression model. And, a Cox proportional hazards model was utilized to analyze survival data. Confounders included gender, age, smoking status, dosage of aspirin and clopidogrel, and BMI. It was found that patients with allele A in CYP2C19*2 and *3 were susceptibility to high PR (OR, 95%CI and P values were 1.34, 1.20-1.50, <0.0001 and 1.42, 1.13-1.79, 0.0029, respectively) after taking clopidogrel. The PR increased along with the number of loss of function (LOF) allele increased and did in order of haplotype*1, *2, and *3. This research suggested that LOF alleles and risk haplotypes in CYP2C19 could significantly attenuate the response to clopidogrel, which resulted in platelet aggregation.

Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma.

BACKGROUND/AIMS: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated. METHODS: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset. RESULTS: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3'-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis. CONCLUSION: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis.

miR-613 inhibits the growth and invasiveness of human hepatocellular carcinoma via targeting DCLK1.

microRNAs (miRNAs) play key regulatory roles in various biological processes. In this study, we aimed to determine the expression and biological roles of miR-613 in hepatocellular carcinoma (HCC). Compared with non-cancerous liver tissues, miR-613 was significantly downregulated in HCC tissues. Ectopic expression of miR-613 significantly suppressed the proliferation and invasion of Hep3B and SMMC-7721 HCC cells. Bioinformatic and luciferase reporter analysis identified doublecortin-like kinase 1 (DCLK1) as a direct target of miR-613. Overexpression of miR-613 inhibited the expression of DCLK1 in HCC cells. There was a significant inverse correlation between miR-613 and DCLK1 protein expression in HCC samples. Small interfering RNA-mediated silencing of DCLK1 phenocopied the suppressive effects of miR-613 in HCC cells. Rescue experiments demonstrated that co-transfection of DCLK1 lacking the 3'-untranslated region partially prevented miR-613-induced suppression of HCC cell proliferation and invasion. In vivo studies confirmed that miR-613 overexpression retarded the growth of Hep3B xenograft tumors in nude mice, coupled with a reduction in the percentage of Ki67-positive tumor cells and DCLK1 protein expression. In conclusion, we provide first evidence for the suppressive activity of miR-613 in HCC, which is causally linked to targeting of DCLK1. Restoration of miR-613 may provide a potential therapeutic strategy for HCC.

[Association between thyroid dysfunction and incidence of atrial fibrillation in patients with stable angina pectoris].

OBJECTIVE: To explore the correlation between incidence of atrial fibrillation (AF) and thyroid dysfunction. METHODS: Patients with stable angina pectoris with thyroid function test results hospitalized at Fuwai Hospital from 2011 Jan to 2011 Dec were included in this analysis (n = 2 541). General clinical data and related biochemical parameters were analyzed. We divided patients into 5 subgroups according to TSH levels: <0.55 mIU/L (n = 105), 0.55-2.49 mIU/L (n = 1599), 2.50-4.77 mIU/L (n = 621), 4.78-9.99 mIU/L (n = 180), >10.00 mIU/L (n = 36). RESULTS: A total of 157 patients were diagnosed with AF (6.8%). (1) Compare to stable angina pectoris patients without AF, stable angina pectoris patients with AF have older age (P < 0.001), higher proportion of female (P = 0.04), uric acid (P < 0.001), NT-proBNP (P = 0.001), larger left atrial diameter (P < 0.001), left ventricular end diastolic diameter (P < 0.001) and lower LVEF (P = 0.038), FT3(P = 0.002), TT3 (P < 0.001). (2) When TSH levels were less than 0.55,0.55-2.49, 2.50-4.77, 4.78-9.99 mIU/L and greater than 10.00 mIU/L, the incidence of AF were 7.6% (8/105) , 5.7% (91/1 599), 7.9% (49/621), 9.4% (17/180) and 22.2% (8/36), respectively. Both a high and a low TSH level were associated with an increased incidence of AF. After adjustment for common risk factor (age, gender and so on) , stepwise multiple logistic regression analysis revealed that TSH levels were significantly related with the incidence of AF. Compared to patients with TSH 0.55-2.49 mIU/L, the adjusted odds ratio of AF for TSH < 0.55, 2.50-4.77, 4.78-9.99, >10.00 mIU/L were 1.37 (95%CI 0.65-2.90, P = 0.415), 1.42 (95CI 0.99-2.04, P = 0.057), 1.73 (95%CI 1.01-2.97, P = 0.048), 4.74 (95%CI 2.10-10.69, P < 0.001), respectively. CONCLUSION: Our results show that incidence of AF increases in proportion to TSH level in patients with stable angina pectoris.

Circulating biomarker- and magnetic resonance-based nomogram predicting long-term outcomes in dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) has a high mortality rate and is the most common indication for heart transplantation. Our study sought to develop a multiparametric nomogram to assess individualized all-cause mortality or heart transplantation (ACM/HTx) risk in DCM patients. METHODS: The present study is a retrospective cohort study. The demographic, clinical, blood test, and cardiac magnetic resonance imaging (CMRI) data of DCM patients in the tertiary center (Fuwai Hospital) were collected. The primary endpoint was ACM/HTx. The least absolute shrinkage and selection operator (LASSO) Cox regression model was applied for variable selection. Multivariable Cox regression was used to develop a nomogram. The concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance of the nomogram. RESULTS: A total of 218 patients were included in the present study. They were randomly divided into a training cohort and a validation cohort. The nomogram was established based on eight variables, including mid-wall late gadolinium enhancement, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction, left ventricular end-diastolic diameter, left ventricular end-diastolic volume index, free triiodothyronine, and N-terminal pro-B type natriuretic peptide. The AUCs regarding 1-year, 3-year, and 5-year ACM/HTx events were 0.859, 0.831, and 0.840 in the training cohort and 0.770, 0.789, and 0.819 in the validation cohort, respectively. The calibration curve and DCA showed good accuracy and clinical utility of the nomogram. CONCLUSIONS: We established and validated a circulating biomarker- and CMRI-based nomogram that could provide a personalized prediction of ACM/HTx for DCM patients, which might help risk stratification and decision-making in clinical practice.

An Experimental Study on the Frictional Behavior of Ultrathin Metal Sheets at Elevated Temperatures.

Hot forming is an effective approach for improving the formability of ultrathin metal sheets, such as those made of stainless steel and pure titanium. However, the increased friction coefficient between the tool and the high-temperature metal sheet negatively affects material flow during hot forming, potentially resulting in severe local thinning or even cracking. This study explores the frictional behavior of 0.1 mm thick ferritic stainless steel (FSS) and commercially pure titanium (CP-Ti) sheets at elevated temperatures. A friction testing apparatus was developed to measure the friction coefficients of these metal sheets from room temperature (25 °C) up to 600 °C. The friction coefficient of the FSS sheet increased monotonically with temperature, whereas that of the CP-Ti sheet first increased and then decreased. Post-friction testing microscopic examination demonstrated that built-up edges formed on the surfaces of the friction blocks when rubbed against the stainless steel, contributing to the higher friction coefficients. This study provides a foundation for understanding frictional behavior during the hot forming of ultrathin metal sheets.